| Autor: |
Mustafa N; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48080 Bilbao, Spain., Mitxelena J; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48080 Bilbao, Spain.; Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain., Infante A; Stem Cells and Cell Therapy Laboratory, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain., Zenarruzabeitia O; Immunopathology Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain., Eriz A; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48080 Bilbao, Spain., Iglesias-Ara A; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48080 Bilbao, Spain., Zubiaga AM; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48080 Bilbao, Spain. |
| Abstrakt: |
Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, E2f2 -/- mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine E2f2 -/- T cells overexpress the proapoptotic genes Fas and FasL and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated E2f2 -/- lymphocytes, but targeted disruption of p53 in E2f2 -/- mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to Fas and FasL gene promoters to repress their expression. in vivo, E2f2 -/- mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies. |
